Drugs used in

Musculoskeletal
Disorders
Dr. Pravin Prasad
MBBS, MD Clinical Pharmacology
Assistant Professor, Maharajgunj Medical
Campus
27 November 2020 (12 Mangsir 2077),
By the end of this session, MBBS
1st year students will be able to:
 Classify Non-steroidal anti-inflammatory
drugs
 Explain the mechanism of action,
indications and adverse effects,
contraindication and overdose
management of:
Aspirin and Paracetamol
List the salient features of different
NSAIDs
Pharmacotherapy for
pain
Non-steroidal anti-
inflammatory drugs (NSAIDs)
Useful in different ways:
Antipyretic
Analgesic
Anti-inflammatory
• Effective in inflammatory pain
 Acts primarily by inhibiting
cyclooxygenase (COX) enzyme
 Do not produce CNS depression, physical
dependence, have no abuse potential
NSAIDs: Classification
Non-selective COX inhibitors
Salicylates: Aspirin
Propionic acid derivatives: Ibuprofen,
Flurbiprofen, Ketoprofen, Naproxen
Fenamate: Mephenamic acid
Enolic acid derivatives: Piroxicam,
Tenoxicam
Acetic acid derivatives: Indomethacin,
Ketorolac
NSAIDs: Classification
Preferential COX-2 inhibitors
Diclofenac, Aceclofenac, Nimesulide,
Meloxicam, Etodolac
Selective COX-2 inhibitors
Celecoxib, Eotricoxib, Parecoxib
Analgesic-antipyretics with poor anti-
inflammatory action
Paracetamol (Acetaminophen),
Nefopam
NSAIDs: Mechanism of
action

Injury
Membrane Phospholipids
Phospholipase A
Arachidonic acid
NSAIDs

Lipooxygenase
Cyclooxygenase

Prostaglandins Leukotrienes
Inflammation pathway
l i p e ( LOX) Leukotrienes
sp ho ge n as
Pho e A 2 pox y
L i
Membrane as
Arachidonic acid Inflammation
phospholipi C yc
ds lo - o
xyg
ena
se (
NSAIDs COX Prostaglandins
)

COX 1:
• Physiological
COX 2:
• House keeping enzyme
Inducible
• Expressed constitutively
Active at the site of
in most cells
inflammation
• Gastric epithelial
Major mediators of
cytoprotection
inflammation
Analgesic effect of
NSAIDs
Peripheral component:
 Inhibits
cyclooxygenase 2
enzyme
• Decreased formation
of bradykinin, TNFa,
interleukins and other
algesic substances
• Free-nerve endings
Analgesic effect of
NSAIDs
Central
component:
Inhibition of PG
synthesis in
spinal dorsal
horn and brain
PG mediated
amplification of
pain impulses
does not occur
Antipyresis by NSAIDs
Lowers body temperature only in fever
Produced through the generation of
pyrogens including, ILs, TNF-alfa,
interferons
• Induces PGE2 production in the
hypothalamus
• Raises the temperature set point of
the hypothalamus
COX-2 (COX-3) mediated
Anti-inflammatory effect
of NSAIDs
Inhibition of COX-2 mediated enhanced
PG synthesis at the site of injury
Inhibition of other inflammatory
molecules
Expressed by endothelial cells- ELAM-1,
ICAM-1
Expressed by inflammatory cells-
selectins, integrins
Inhibit generation of free radicals,
NSAIDs: Mechanism of
action: Summary
Inhibits cyclooxygenase enzyme (COX)
COX-2 inhibition responsible
Decreased formation of prostaglandins
(PGs) at the site of injury and in brain
PGs responsible for pain (algesia),
inflammation, fever (pyrexia)
Therapeutic effect seen
Analgesic, Anti-inflammatory,
Antipyretic
Aspirin
Acetylsalicylic acid gets converted to salicylic acid
Pharmacological actions:
Analgesic
• Effectively relieves inflammation, tissue injury,
connective tissue and integumental pain
Antipyretic
• Resets hypothalamic thermostat
• Reduces fever by promoting heat loss
Anti-inflammatory
• Exerted at high doses (3-6 g/ day or 100
Aspirin
Pharmacological actions:
Blood
• Small doses irreversibly inhibits TXA2
synthesis by platelets.
Interferes with platelet aggregation
• Bleeding time is prolonged
• Long-term intake of large dose decreases
synthesis of clotting factors in liver
Predisposes to bleeding
Aspirin
Pharmacological actions
Gastro-intestinal effects
• Irritate gastric mucosa, cause
epigastric distress, nausea and
vomiting.
• Stimulates CTZ.
Urate excretion:
• High dose reduces renal tubular
excretion of urate
Aspirin (Acetylsalicylic
Acid)
Non-selective COX inhibitor (salicylates)
COX-1 inhibition: anti-platelet
aggregatory
• Inhibited irreversibly
• 75-150 mg/d
• Decreased TXA2 synthesis in the
platelets
Effects lasts till formation of new
platelets (7 days)
Aspirin (Acetylsalicylic
Acid)
Non-selective COX inhibitor (salicylates)
COX-2 inhibition: analgesia
• 600 mg, 3-4 times a day
• Inhibits PG synthesis at the site of injury
(peripheral action)
Decreases sensitization of pain
receptors to pain inducing stimuli
• Inhibits PG synthesis in the spinal dorsal
horn neurons and brain (central action)
Raised threshold to pain perception
Aspirin (Acetylsalicylic
Acid)
Non-selective COX inhibitor (salicylates)
COX-2 inhibition: antipyretic
• 600 mg, 3-4 times a day
• Formation of PGs in brain in response
to pyrogens decreased
• Resets the hypothalamic thermostat
and rapidly reduces fever by
promoting heat loss (sweating,
cutaneous vasodilatation)
Aspirin (Acetylsalicylic
Acid)
Non-selective COX inhibitor (salicylates)
COX-2 inhibition: anti-inflammatory
• 3-6 gm/d
• Decreased PG synthesis at the site of
injury
• Inflammatory changes (vasodilatation,
migration of cells, release of
mediators, etc.) cannot occur
• Additional action: quenching of free
Aspirin: Indications
As anti-platelet aggregatory (75-150
mg/day)
Post myocardial infarction, post stroke
As analgesic (300-600 mg, 3-4 times a
day)
As antipyretic (same dose)
Paracetamol safer
Acute rheumatic fever (4-5 gm/day)
Aspirin: Adverse effects
Hypersensitivity/ Idiosyncratic reaction
At analgesic/ antipyretic doses:
Nausea, vomiting, epigastric distress,
increased occult blood loss
Gastric mucosal damage, peptic ulcer
Occasionally produce mild hepatitis
Prolong bleeding time
Aspirin: Adverse effects
Anti-inflammatory doses:
Salicylism
• Dizziness, tinnitus, vertigo, reversible
impairment of hearing and vision,
excitement, hyperventilation and
electrolyte imbalance
Liver damage in children
Reye’s syndrome in children with viral
infection
Aspirin:
Contraindications
History of:
Hypersensitivity to aspirin
Peptic ulcer
Having bleeding tendencies
Children with viral infections (chicken
pox, influenza)
Pregnancy, breast-feeding mother
Aspirin: Overdose
features
Adult fatal dose: 15-30 grams
Clinical features:
Vomiting, dehydration, Electrolyte imbalance
Acidotic breathing (deep, laboured and gasping)
Hyper/hypoglycaemia
Petechial haemorrhages
Restlessness, delirium, hallucinations,
hyperpyrexia, convulsions, coma
Death: respiratory failure and cardiovascular
collapse
Aspirin: Overdose
treatment
Symptomatic and supportive
Hyperpyrexia: External cooling
Dehydration and electrolyte imbalance:
intravenous fluids (crystalloids)
Hypoglycaemia: glucose infusion
Petechial haemorrhages: platelet or
blood transfusion, vitamin K
Acetaminophen
(Paracetamol)
Potent analgesic and anti-pyretic action
Analgesic action:
Decreased PG synthesis in spinal dorsal
horn neurons and brain  PG mediated
amplification of pain impulses does not
occur  Raises pain threshold
Antipyretic action similar to aspirin
Acetaminophen
(Paracetamol)
Safer than aspirin as it does not:
Stimulate respiration
Affect acid-base balance, platelet
function, and clotting factors
Increase cellular metabolism
Show any effect on the cardiovascular
system
Show significant gastric irritation
Paracetamol: Indications
As analgesic
Over-the-counter drug
Useful in non-inflammatory pain:
headache, mild migraine,
musculoskeletal pain, dysmenorrhoea
Osteoarthritis
As antipyretic
Safe for children as well
Paracetamol: Adverse
effects
Safe and well tolerated at usual doses
Occasional: Nausea, rashes
Rare: leukopenia
Overdose: Acute Paracetamol poisoning
Not recommended in premature infants
(< 2 kg)
Paracetamol overdose
>10gm in adult (>150mg/kg)
Fatal dose: >250mg/kg
Nausea, vomiting, abdominal pain, liver
tenderness
Hepatic necrosis, renal tubular necrosis,
hypoglycaemia, coma, jaundice
Fulminating hepatic failure and death at
high plasma levels
Paracetamol overdose:
Treatment
Maintain airway, breathing and
circulation
Decontamination:
Activated charcoal (orally or through
Nasogastric tube)
• Prevents further absorption of drugs
Supportive measures
Paracetamol overdose:
Treatment
Specific antidote:
N-acetylcysteine:
• Initiate as early as possible, doubtful if
initiated after 16 hours of ingestion
• Intravenous: 150 mg/kg over 15 mins
followed by 150 mg/kg over next 20
hours
• Oral: 75mg/kg, repeat every 4-6 hours
for 2-3 days
Propionic acid
derivatives
Ibuprofen, Naproxen, Ketoprofen,
Flurbiprofen
Introduced as better alternative to
aspirin
• Less severe gastro-intestinal side
effects
• Headache, dizziness, blurring of vision,
tinnitus
Safest traditional NSAIDs
Anthranilic acid
derivatives
Mephenamic acid
Analgesic, antipyretic and weaker anti-
inflammatory
Uses:
Analgesic: muscle, joint and soft tissue
pain; dysmenorrhoea
Adverse effects:
Diarrhoea, epigastric distress,
haemolytic anaemia
Enolic acid derivatives
Piroxicam, Tenoxicam
Long-acting potent NSAID with potent
anti-inflammatory and good analgesic-
antipyretic action
Indications:
• As long term anti-inflammatory drugs
 Rheumatoid arthritis, osteoarthritis,
ankylosing arthritis
Acetic acid derivatives
Ketorolac, Indomethacin, Nabumetone
Ketorolac:
Potent analgesic and modest anti-
inflammatory
activity
Indications:
• Postoperative, dental and acute
musculoskeletal pain
• Renal colic, migraine, metastasis-
Acetic acid derivatives
Indomethacin:
Potent anti-inflammatory drug with
prompt antipyretic action
Relieves only inflammatory or tissue
injury-related pain
Acetic acid derivatives
Indomethacin:
Uses:
• Medical closure of patent ductus
arteriosus
• As a reserved drug (in conditions
requiring potent anti-inflammatory
effect)
Ankylosing spondylitis, acute
exacerbation of destructive
Preferential COX-2
inhibitors
Nimesulide, Diclofenac sodium,
Aceclofenac, Meloxicam, Etodolac
Nimesulide
Moderate COX-2 selectivity
• Anti-inflammatory action may be
exerted by other mechanisms as well
Activity has been rated comparable to
other NSAIDs
Preferential COX-2
inhibitors
Nimesulide
Used primarily for:
• Short-lasting painful inflammatory
conditions like sports injuries, sinusitis
and other ear-nose-throat disorders
• Dental surgery, postoperative pain
• Bursitis, low backache,
dysmenorrhoea, osteoarthritis
• Fever
Preferential COX-2
inhibitors
Nimesulide
Adverse effects:
• Gastrointestinal side effects:
epigastric pain, heart burn, nausea,
loose motions
• Dermatological side effects: rash,
pruritus
• CNS side effects: somnolence,
dizziness
Diclofenac
Has all three effects:
Analgesic, Antipyretic and Anti-inflammatory
Some degree of COX-II selectivity seen
Good tissue penetrability
Longer acting
Side effects:
Milder as compared to Non-selective NSAIDs
Lacks anti-platelet action: increase risk of
heart attack and stroke
Selective COX-2
inhibitors
Celecoxib, Etoricoxib, Parecoxib
Anti-inflammatory, analgesic and antipyretic
actions with low ulcerogenic potential
Better tolerated than traditional NSAIDs
Abdominal pain, dyspepsia and mild
diarrhoea are the common side effects
Rashes, oedema and a small rise in BP
Etoricoxib: dry mouth, aphthous ulcers,
taste disturbance and paresthesias
Classwork!
Non-
Selective
Characteris selective
COX
tics COX
inhibitors
inhibitors
Mechanism
of action
Advantages
Disadvantage
s
Conclusion: NSAIDs
NSAIDs acts by inhibiting COX enzymes
COX-II selectivity results in less gastro-
intestinal side effects and more CV side
effects
Aspirin exerts multiple actions by
blocking both COX enzymes
Ibuprofen is a safer alternative for aspirin
Diclofenac has some selectivity for COX-II
Paracetamol has weak anti-inflammatory
That would be all from
my side
Further reading:
Topical NSAIDs
• Ophthalmic
• Gels, Sprays
Questions??
Thank you!!